Prenatal betamethasone–postnatal N‐methyl‐D‐aspartic acid model of spasms: Update on mechanisms and treatments

Infantile epilepsy spasms syndrome (IESS), formerly known as infantile spasms or West Syndrome, is a severe epilepsy syndrome affecting about 3 in 10,000 newborns in the United States. Characterized by clusters of epileptic spasms, interictal hypsarrhythmia, and developmental delays, IESS has diverse causes, including structural-metabolic, genetic, infectious-immune, and unknown factors. FDA-approved therapies/medications, ACTH and vigabatrin, have limited efficacy and significant side effects, necessitating further research into better therapies. Our prenatal betamethasone-postnatal NMDA rat model provides valuable insights into IESS mechanisms and treatment responses. Mimicking human IESS in semiology, EEG patterns, and drug responsiveness, this model has been independently validated and adapted for infant mice. EEG recordings, crucial for validation and drug discovery, help assess treatment efficacy by tracking clinical spasms and the elimination of large amplitude irregular EEG waves occurring in clusters. Automated and manual EEG quantification enhance the model's precision. Proteomic analyses highlight significant differences in proteins like SNAP25 and creatine kinase between spasms and non-spasms groups. Imaging studies in the model reveal early activation of stress-responsive brain regions, consistent with epidemiological evidence linking prenatal stress to an increased risk of IESS in humans. ACTH and its analog, AQB-565, effectively suppress spasms, with AQB-565 potentially reducing corticosteroid-related side effects. The C5a receptor antagonist PMX53 shows efficacy in males, suggesting inflammation may be a therapeutic target. Neonatal β-estradiol increases GABAergic neurons but has limited impact on spasms and poses reproductive risks. These findings highlight the complexity of IESS and the need for targeted, sex-specific, and mechanism-based therapies to improve treatment outcomes for patients. PLAIN LANGUAGE SUMMARY: Infantile epilepsy spasms syndrome (IESS) is a severe epilepsy syndrome affecting 3 in 10 000 newborns in the United States, causing clusters of brief convulsions, abnormal brain activity, and developmental delays. It has various causes, including genetic and perinatal factors. Current medications, such as ACTH and vigabatrin, have limited effectiveness and side effects, highlighting the need for better options. We use a rodent model to study IESS and evaluate treatments. Some therapies, like AQB-565, show promise in reducing seizures with fewer side effects. Our findings suggest that personalized, targeted treatments based on individual causes and sex differences could improve outcomes.